AIM: To investigate the prognostic factors in patients with hepatocellular carcinoma (HCC) accompanied by microscopic portal vein invasion (PVI).METHODS: Of the 267 patients with HCC undergoing hepatic resection at Aso Iizuka Hospital, 71 had PVI. After excluding 16 patients with HCC that invaded the main trunk and the first and second branches of the portal vein, 55 patients with microscopic PVI were enrolled.RESULTS: The patients with HCC accompanied by microscopic invasion were divided into two groups: solitary PVI (PVI-S: n = 44), and multiple PVIs (PVI-M: n = 11). The number of portal vein branches invaded by tumor thrombi was 5.4 +/- 3.8 (2-16) in patients with PVI-M. In cumulative survival, PVI-M was found to be a significantly poor prognostic factor (P = 0.0019); while PVI-M and non-anatomical resection were significantly poor prognostic factors in disease-free survival (P = 0.0213, and 0.0115, respectively). In patients with PVI-M, multiple intrahepatic recurrence was more common than in the patients with PVI-S (P = 0.0049). In patients with PVI-S, non-anatomical resection was a significantly poor prognostic factor in disease-free survival (P = 0.0370). Operative procedure was not a significant prognostic factor in patients with PVI-M.CONCLUSION: The presence of PVI-M was a poor prognostic factor in patients with HCC, accompanied by microscopic PVI. Anatomical resection is recommended in these patients with HCC. Patients with HCC and PVI-M may also be good candidates for adjuvant chemotherapy.